1,6-naphthyridine anti-convulsants

ABSTRACT

Compounds of formula (I) and pharmaceutically acceptable salts thereof:whereR1 is hydrogen, C1-6 alkyl optionally substituted by hydroxy or C1-4alkoxy, or C1-6 alkylphenyl;R2 is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, C1-6 alkylO-, C1-6 alkylS-, C1-6 alkyl, C3-6cycloalkyl,C3-6cycloalkyl-C1-4alkyl-, C1-6alkenyl, C1-6alkynyl, CF3, CF3O, CF3CO-, C1-6alkylCO-, C3-6cycloalkylCO-,C3-6cycloalkyl-C1-4alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-,or -NR3R4 whereR3 is hydrogen or C1-4 alkyl, andR4 is hydrogen, C1-4alkyl, -CHO,-CO2C1-4alkyl or -COC1-4alkyl;or two R2 groups form a saturated carbocyclic ring optionally interrupted by oxygen;and X is selected from hydrogen, halogen, cyano, alkyl and alkoxy;are useful in the treatment and prophylaxis of inter alia epilepsy.

This application is the national phase of PCT/GB98/01575 filed May 29,1998.

This invention relates to novel compounds, to processes for preparingthem, and to their use as therapeutic agents.

EP-A-0556008 (Shionogi) discloses condensed imidazopyridine derivativeswith psychotropic activity, including the compound1,6naphthyridine-6(5H)-carboxylic acid, 4-azido-3-[[(1,1-dimethylethoxy)carbonyl]amino]-7,8-dihydro, ethyl ester.

It has now been surprisingly found that carboxamide compounds of formula(I) below possess anti-convulsant activity and are therefore believed tobe useful in the treatment and/or prevention of anxiety, mania,depression, panic disorders and/or aggression, disorders associated witha subarachnoid haemorrhage or neural shock, the effects associated withwithdrawal from substances of abuse such as cocaine, nicotine, alcoholand benzodiazepines, disorders treatable and/or preventable withanti-convulsive agents, such as epilepsy including post-traumaticepilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia,Alzheimer's disease and other degenerative diseases such as Huntingdon'schorea, schizophrenia, obsessive compulsive disorders (OCD),neurological deficits associated with AIDS, sleep disorders (includingcircadian rhythm disorders, insomnia & narcolepsy), tics (e.g. Giles dela Tourette's syndrome), traumatic brain injury, tinnitus, neuralgia,especially trigeminal neuralgia, neuropathic pain, dental pain, cancerpain, inappropriate neuronal activity resulting in neurodysthesias indiseases such as diabetes, MS and motor neurone disease, amyotrophiclateral sclerosis, ataxias, muscular rigidity (spasticity) andtemporomandibular joint dysfunction.

Accordingly, the present invention provides a compound of formula (I) orpharmaceutically acceptable salt thereof:

where

R¹ is hydrogen, C₁₋₆alkyl optionally substituted by hydroxy or C₁₋₄alkoxy, or C₁₋₆alkylphenyl;

R² is hydrogen or up to three substituents selected from halogen, NO₂,CN, N₃, C₁₋₆ alkylO-, C₁₋₆ alkylS-, C₁₋₆ alkyl, C₃₋₆cycloalkyl,

C₃₋₆cycloalkyl-C₁₋₄alkyl-, C₁₋₆alkenyl, C₁₋₆alkynyl, CF₃, CF₃O, CF₃CO—,C₁₋₆alkylCO-, C₃₋₆cycloalkylCO-,

C₃₋₆cycloalkyl-C₁₋₄alkylCO-, phenyl, phenoxy, benzyloxy, benzoyl,phenyl-C 14alkyl-,

or —NR³R⁴ where

R³ is hydrogen or C₁₋₄ alkyl, and

R⁴ is hydrogen, C ₁₋₄alkyl, —CHO,

—CO₂C₁₋₄alkyl or —COC₁₋₄alkyl;

or two R² groups form a saturated carbocyclic ring optionallyinterrupted by oxygen;

and X is selected from hydrogen, halogen, cyano, alkyl and alkoxy.

The compounds of this invention are typicallynaphthyridin-3-yl-benzamides.

In the formula (I), alkyl groups, including alkyl groups that are partof another moiety, may be straight chain or branched. Aromatic rings,especially phenyl groups, (including rings that are part of anothermoiety), may optionally be substituted with one or more independentlyselected halogen or C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy orC₁₋₆alkylcarbonyl.

Suitable C₃₋₆ cycloalkyl groups include cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl.

Suitable halo substituents include fluoro, chloro, iodo and bromo.

A suitable group of compounds of formula (I) have

R¹ as hydrogen, methyl or benzyl

R² as hydrogen, methoxy, ethoxy, iso-propyloxy, methyl, ethyl,iso-propyl, tert-butyl, pivaloyl, trifluoromethyl, chloro, bromo, ornitro.

Examples of compounds of formula (I) are:

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-benzamide

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2-methoxy-4-t-butylbenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propoxybenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxybenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2-methoxy-5-pivaloylbenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-trifluoromethylbenzarnide and its monohydrochloride

N-(6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-t-butylbenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamideand its monohydrochloride

N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzatnideand its monohydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl benzamide

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-cyclohexylbenzarnide

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-benzoylbenzamide

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-ylcarboxamide

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-t-butyl-3-trifluoromethylbenzamide

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propylbenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-nitrobenzamidehydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-t-butylbenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-n-propyl-oxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3,5-dichloro-4-methoxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propylbenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-n-propyloxy-3-trifluoromethylbenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-iodo-4-methoxybenzamidehydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propyl-3-trifluoromethylbenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-n-propyloxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide, hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl]-4-ethyl-3-trifluoromethylbenzamide

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propyloxy-3-trifluoromethylbenzamide,hydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-iodo-4-methylbenzamidehydrochloride

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-azido-3-iodo-benzamide

N-(2-Bromo-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide

N-(2-Bromo-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide,hydrochloride

N-(2,6-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxy-benzamide

N-(2,6-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(2-Cyano-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide

N-(2-Chloro-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide

N-(2-Chloro-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide.

When synthesised, these compounds are often in salt form, typically thehydrochloride or trifluoroacetate, and such salts also form part of thisinvention. Such salts may be used in preparing pharmaceuticallyacceptable salts. The compounds and their salts may be obtained assolvates, such as hydrates, and these also form part of this invention.

The above-listed compounds and pharmaceutically acceptable saltsthereof, especially the hydrochloride, and pharmaceutically acceptablesolvates, especially hydrates, form a preferred aspect of the presentinvention.

The administration of such compounds to a mammal may be by way of oral,parenteral, sub-lingual, nasal, rectal, topical or transdermaladministration.

An amount effective to treat the disorders hereinbefore describeddepends on the usual factors such as the nature and severity of thedisorders being treated and the weight of the mammal. However, a unitdose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doseswill normally be administered once or more than once per day, forexample 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day,such that the total daily dose is normally in the range, for a 70 kgadult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, forexample 1 to 6 mg/kg/day.

It is greatly preferred that the compound of formula (I) is administeredin the form of a unit-dose composition, such as a unit dose oral,including sub-lingual, nasal, rectal, topical or parenteral (especiallyintravenous) composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, in particular shaped oral compositions, since they are moreconvenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well known methods in the art.

Suitable fillers for use include cellulose, mannitol, lactose and othersimilar agents. Suitable disintegrants include starch,polyvinylpyrrolidone and starch derivatives such as sodium starchglycollate. Suitable lubricants include, for example, magnesiumstearate. Suitable pharmaceutically acceptable wetting agents includesodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, alumninium stearate gel or hydrogenated edible fats,emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained releaseformulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilised by exposure to ethylene oxide before suspendingin the sterile vehicle. Advantageously, a surfactant or wetting agent isincluded in the composition to facilitate uniform distribution of thecompound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

Accordingly, in a further aspect, the present invention provides apharmaceutical composition for use in the treatment and/or prophylaxisof anxiety, mania, depression, panic disorders and/or aggression,disorders associated with a subarachnoid haemorrhage or neural shock,the effects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines, disorders treatableand/or preventable with anti-convulsive agents, such as epilepsyincluding post-traumatic epilepsy, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease and other degenerativediseases such as Huntingdon's chorea, schizophrenia, obsessivecompulsive disorders (OCD), neurological deficits associated with AIDS,sleep disorders (including circadian rhythm disorders, insomnia &narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumaticbrain injury, tinnitus, neuralgia, especially trigeminal neuralgia,neuropathic pain, dental pain, cancer pain, inappropriate neuronalactivity resulting in neurodysthesias in diseases such as diabetes, MSand motor neurone disease, ataxias, muscular rigidity (spasticity),amyotrophic lateral sclerosis and temporomandibular joint dysfunction,which comprises a compound of formula (I), or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.

The present invention also provides a method of treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, MS and motor neurone disease, ataxias, muscular rigidity(spasticity), amyotrophic lateral sclerosis and temporomandibular jointdysfunction, comprising administering to the sufferer in need thereof aneffective or prophylactic amount of a compound of formula (I), or apharmaceutically acceptable salt or solvate thereof.

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate thereof,for the manufacture of a medicament for the treatment and/or prophylaxisof anxiety, mania, depression, panic disorders and/or aggression,disorders associated with a subarachnoid haemorrhage or neural shock,the effects associated with withdrawal from substances of abuse such ascocaine, nicotine, alcohol and benzodiazepines, disorders treatableand/or preventable with anti-convulsive agents, such as epilepsyincluding post-traumatic epilepsy, Parkinson's disease, psychosis,migraine, cerebral ischaemia, Alzheimer's disease and other degenerativediseases such as Huntingdon's chorea, schizophrenia, obsessivecompulsive disorders (OCD), neurological deficits associated with AIDS,sleep disorders (including circadian rhythm disorders, insomnia &narcolepsy), tics (e.g. Giles de la Tourette's syndrome), traumaticbrain injury, tinnitus, neuralgia, especially trigeminal neuralgia,neuropathic pain, dental pain, cancer pain, inappropriate neuronalactivity resulting in neurodysthesias in diseases such as diabetes, MSand motor neurone disease, ataxias, muscular rigidity (spasticity),amyotrophic lateral sclerosis and temporomandibular joint dysfunction.

In a further aspect the invention provides the use of a compound offormula (I), or a pharmaceutically acceptable salt or solvate, thereofas a therapeutic agent, in particular for the treatment and/orprophylaxis of anxiety, mania, depression, panic disorders and/oraggression, disorders associated with a subarachnoid haemorrhage orneural shock, the effects associated with withdrawal from substances ofabuse such as cocaine, nicotine, alcohol and benzodiazepines, disorderstreatable and/or preventable with anti-convulsive agents, such asepilepsy including post-traumatic epilepsy, Parkinson's disease,psychosis, migraine, cerebral ischaemia, Alzheimer's disease and otherdegenerative diseases such as Huntingdon's chorea, schizophrenia,obsessive compulsive disorders (OCD), neurological deficits associatedwith AIDS, sleep disorders (including circadian rhythm disorders,insomnia & narcolepsy), tics (e.g. Giles de la Tourette's syndrome),traumatic brain injury, tinnitus, neuralgia, especially trigeminalneuralgia, neuropathic pain, dental pain, cancer pain, inappropriateneuronal activity resulting in neurodysthesias in diseases such asdiabetes, MS and motor neurone disease, ataxias, muscular rigidity(spasticity) and temporomandibular joint dysfunction.

Another aspect of the invention provides a process for the preparationof compounds of formula (I), which comprises reacting a compound offormula (II)

where R^(1A) is R¹ as defined for formula (I) or a group convertible toR¹ with a compound of formula (III)

where Y is Cl or OH, and R^(2A) is R² as defined for formula (I) or agroup or groups convertible to R²,

and where required converting a R^(1A) or R^(2A) group to a R¹ or R²group, converting one X, R¹ or R² group to another X, R¹ or R² group,converting a salt product to the free base or another pharmaceuticallyacceptable salt, or converting a free base product to a pharmaceuticallyacceptable salt.

Reaction of a compound of formula (HII) which is a benzoyl chloridederivative (Y═Cl) will lead directly to the hydrochloride salt. Suitablesolvents include tetrahydrofuran and ethyl acetate. When the compound offormula (III) is a benzoic acid derivative (Y═OH), conventionalconditions for condensation of aromatic acids with amines may be used,for example reacting the components in a mixture of(dimethylaminopropyl)-ethyl-carbodiimide/hydroxybenzotriazole in asuitable solvent, such as dimethyl formamide.

Conversions of an R^(1A) or R^(2A) group to a R¹ or R² group typicallyarise when a protecting group is needed during the above couplingreaction or during the preparation of the reactants by the proceduresdescribed below. Interconversion of one X, R¹ or R² group to anothertypically arises when one compound of formula (I) is used as theimmediate precursor of another compound of formula (I), or when it iseasier to introduce a more complex or reactive substituent at the end ofa synthetic sequence.

Compounds of formula (II) may be prepared starting from a compound offormula (IV), that is a dinitro-1-methyl-2-pyridone

by reaction with a compound of formula (V)

in a solution of ammonia in a suitable solvent such as methanol, toobtain a compound of formula (VI) using a procedure similar to that ofS. Takada et al, J. Med. Chem, 1996, 39, 2844.

Compounds of formula (VI) may be converted to compounds of formula (II)wherein X is hydrogen by hydrogenation or reduction of the nitro group.For example, a compound of formula (VI) may be hydrogenated by treatmentwith hydrogen in a suitable solvent such as methanol in the presence ofa palladium/carbon catalyst. Alternatively, a compound of formula (VI)may be reduced with stannous chloride in concentrated hydrochloric acidin a suitable solvent such as ethanol.

Compounds of formula (IV) may be prepared using the procedure of E.Matsumura, M. Ariga and Y. Tohda, Bull. Chem. Soc. Japan, 52 (8),2413-2419 (1979).

Compounds of formula (II) wherein X is hydrogen can be converted tocompounds wherein X is other using methods known in the art anddescribed hereinbelow in the Descriptions.

Compounds of formula (III) may be prepared by further substitution ofcommercially available benzoic acid derivatives using conventionalprocedures, or by oxidation of corresponding substituted benzylalcohols. Alternatively benzoic acids can be prepared fromcorrepondingly substituted phenols, for example by formation of theacetate, coversion to an acetophenone and then to the desired acid.

The preparation of compounds of formula (II) is illustrated by thefollowing Descriptions; the preparation of compounds of formula (III) isillustrated by the following Preparations; the preparation of compoundsof this invention is illustrated by the following Examples. The utilityof compounds of this invention is shown by the Pharmacological Data thatfollow the Examples.

Description 1

6-Benzyl-3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridine

3,5-Dinitro-1-methyl-2-pyridone (1.99 g; 10 mmol) [prepared according toE. Matsumura, M. Ariga and Y. Tohda, Bull. Chem. Soc. Japan, 1979, 52,2413 ] was added to a solution of ammonia in methanol (1.1M; 100 ml; 110mmol) and then treated with 1-benzyl-4-piperidone (2.27 g; 12 mmol). Theresulting mixture was heated at 60° C. for 5 h, cooled to roomtemperature and evaporated to dryness in vacuo. The residue was purifiedby chromatography through SiO₂ eluting with 50% ethyl acetate/60-80°pet. ether to give the title compound (2.5 g; 93%). Recrystallisationfrom ethyl acetate −60-80° petroleum ether gave the title compound as apale yellow, microcrystalline solid, mp 108° C.

¹H NMR (250MHz; CDCl₃) δ: 3.03 (2H, t, J=6 Hz), 3.28 (2H, t, J=6 Hz),3.83 and 3.87 (each 2H, 2s), 7.38-7.49 (5H, m), 8.21 (1H, d, J=2 Hz),9.33 (1H, d, J=2 Hz);

^(m)/_(z): 270.122997; C₁₅H₁₆N₃O₂ requires 270.122997. Found: C, 66.75;H, 5.48; N, 15.61%. C₁₅H₁₅N₃O₂ requires: C, 66.84; H, 5.56; N, 15.60%.

Description 2

3-Amino-6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine

6-Benzyl-3-nitro-5,6,7,8-tetrahydro-[1,6]-naphthyridine (790 mg; 2.93mmol) was dissolved in ethanol (100 ml), the solution heated at 50° C.and treated with a solution of stannous chloride dihydrate (2.65 g;11.73 mmol) in conc. hydrochloric acid (10 ml). After 10 min, thereaction mixture was concentrated under reduced pressure, neutralised byaddition of 2M aqueous sodium hydroxide and extracted with DCM. Theextracts were combined, washed with water, saturated brine, dried(MgSO₄) and evaporated to dryness in vacuo. The brown residue wasdissolved in methanol and SiO₂ added. The volatiles were removed underreduced pressure and the dried SiO₂ placed on the top of a silica columnand subjected to chromatography, eluting with ethanol in ethyl acetate(020%) ethanol gradient. The title compound was obtained as a whitepowder (275 mg; 39%).

¹H NMR (250MHz, (CD₃)₂SO) δ: 2.33 (4H, br m), 3.25 (2H, s), 3.45 (2H, brs), 4.84 (2H, br s, exchangeable), 6.37 (1H, br s), 7.11-7.22 (5H, m),7.56 (1H, br s)

^(m)/_(z) Found: 240.150073. C₁₅H₁₈N₃ requires 240.15837.

Description 3

6-Methyl-3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridine

3,5-Dinitro-1-methyl-2-pyridone (5.97 g; 30 mmol) was treated with 1.22Mammonia in methanol (300 ml) then 1-methyl-4-piperidone (3.73 g, 33mmol) and the mixture heated at 60° for 5 h, then allowed to stand atambient temp for 72 h. Evaporation in vacuo gave an orange/red residuewhich was triturated in dichloromethane and diethyl ether, collected byfiltration, washed with diethyl ether and dried in air. Chromatographythrough silica gel, eluting with ethyl acetate, gave the title compoundas a red solid (3.4 g, 59%).

¹H NMR (250MHz; CDCl₃): δ: 2.53 (3H, s), 2.85 (2H, t, J=6 Hz), 3.18 (2H,t, J=6 Hz), 3.69 (2H, s), 8.14 (1H, d, J=2 Hz), 9.23 (1H, d, J=2 Hz);

^(m)/_(z) (API): 192.18 (M−H); 194.09 (M+H)⁺

Description 4

3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine

6-Methyl-3-nitro-5,6,7,8-tetrahydro[1,6]naphthyridine (2.72 g, 1.41mmol) was dissolved in methanol (100 ml) and treated with 10% palladiumon carbon (1.0 g). The mixture was hydrogenated for 2 h. The catalystwas removed by filtration through Celite, the filter bed washed withmethanol and the filtrate evaporated to dryness under reduced pressureto give a yellow solid, which was triturated under diethyl ether and thesolids collected by filtration, washed with diethyl ether and dried invacuo (1.89 g, 83%)

¹H NMR (250MHz, CDCl₃) δ_(H): 2.46 (3H, s), 2.75 (2H, t, J=6 Hz), 2.95(2H, t, J=6 Hz), 3.50 (2H, s), 3.56 (2H, br s, exchangeable), 6.65 (1H,d, J=2 Hz), 7.92 (1H, d, J=2 Hz);

^(m)/_(z) (API): 164 (M+H)⁺

Description 5

3-Amino-2-chloro-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine

3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine D4 (900 mg, 5.52mmol) was dissolved in acetic acid (50 ml) before being treatedportionwise with N-chlorosuccinimide (1.11 g, 8.28 mmol) 20 min. Thereaction mixture was stirred overnight at room temperature under argon.The reaction mixture was diluted with water (125 ml), basified to pH10with solid K₂CO₃ and extracted with dichloromethane (×2). The combinedorganic extracts were washed with sodium bicarbonate, dried (MgSO₄) andevaporation in vacuo gave a crude black solid. Flash chromatographyusing dichloromethane (10% MeOH) gave thetitle compound as a pale orangesolid.

¹H NMR (CDCl₃) δ: 2.46 (3H, s), 2.73 (2H, t), 2.92 (2H, t), 3.49 (2H,s), 3.91 (1H, s), 6.72 (1H, s).

Description 6

3-Amino-2-bromo-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine

D4 (978 mg, 6 mmol) was dissolved in acetic acid (10 ml) containing 2Msulphuric acid (2 ml). Bromine (0.31 ml, 6 mmol) was added dropwise withstirring over a period of approximately 25 min. After 2 h, theprecipitated solid was removed by filtration and washed with ether togive a pale yellow solid which was dissolved in water. The solution wasbasified with 2M NaOH and extracted with ethyl acetate. The combinedextracts were washed with brine, dried (MgSO₄) and evaporation in vacuogave the crude product as a pale yellow solid (444 mg). The abovefiltrate from the reaction mixture was concentrated by evaporation invacuo, diluted with water and made basic with 2M sodium hydroxide. Themixture was extracted with dichloromethane and the extract dried (MgSO₄)and evaporated to give a crude brown solid which was purified bychromatography on silica gel eluting with dichloromethane:methanol:aq.ammonia (0.880) (ratio 19:1:0.1). The title compound was obtained as awhite solid (248 mg).

¹H NMR (250MHz, CDCl₃) δ: 2.45 (3H, s), 2.72 (2H, t, J=6 Hz), 2.93 (2H,t, J=6 Hz), 3.46 (2H, s), 3.94 (2H, brs), 6.68 (1H, s).

Description 7

3-Amino-2,6-dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridine

D6 (250 mg, 1.03 mmole) was dissolved in DMF (4 ml) and bistriphenylphosphine palladium (II) chloride (36 mg) and lithium chloride(130 mg) added. A solution of tetramethyltin (190 mg) in DMF (1 ml) wasadded and the mixture heated at 100° C. under argon for 36 h. A furtherportion (180 mg) of tetramethyltin and a further portion of palladiumcatalyst (15 mg) were added and heating contained for a further 24 h.The reaction mixture was evaporated to dryness and chromatographed onsilica gel eluting with dichloromethane:methanol:aq ammonia (0.880)(ratio 19:2:0.1). The title compound was obtained as a pale yellow solid(147 mg).

₁H NMR (250MHz, d₆ acetone) δ: 2.12 (3H, s), 2.30 (3H, s), 2.68 (4H, s),3.40 (2H, s), 4.28 (ca 2H, br), 6.51 (1H, s); m/z (API⁺): 178 (MH⁺,100%).

Preparation 1

4-iso-Propyloxy-3-trifluoromethylbenzoic acid

Methyl 3-bromo-4-iso-propyloxybenzoate (828 mg; 3.03 mmol) was dissolvedin DMF (25 ml) and treated with potassium trifluoroacetate (922 mg; 6.06mmol), copper (I) iodide (1.15 g; 6.06 mmol) and toluene (50 ml). Theresulting mixture was heated at reflux for 1.5 h under Dean and Starkconditions with removal of ca 50 ml of distillate. The resulting mixturewas heated at reflux for 18 h then cooled to room temperature, beforebeing poured into a mixture of Et₂O (100 ml) and HO (100 ml). Thetwo-phase mixture was stirred at room temperature for 0.5 h thenfiltered through Celite. The two phases in the filtrate were separated,the aq. phase further extracted with Et₂O (50 ml) and the organicextracts combined, washed with saturated, aq. Na₂S₂O₃, H₂O, saturatedbrine, dried (MgSO₄) and evaporated to dryness under reduced pressure togive a brown oil. This brown oil was dissolved in MeOH (ca 20 ml) andtreated with 2M aq. sodium hydroxide solution (2 ml; 4 mmol) and theresulting solution heated at reflux for 3h. The volatiles were removedunder reduced pressure and the residue partitioned between EtOAc andH₂O. The phases were separated, the aq. phase acidified to pH1 with 2Mhydrochloric acid in the presence of EtOAc and the phases separated. Theaq. phase was further extracted with EtOAc, the extracts combined,washed with H₂O, saturated brine, dried (MgSO₄) and evaporated todryness underreduced pressure to give the title compound as a whitesolid. (671 mg; 89%).

₁H NMR (250MHz; (CD₃)₂CO) δ:1.02 (6H, d, J=6 Hz), 4.53-4.63 (1H, m),7.01 (1H, , J=9 Hz), 7.85-7.88 (2H, m); ^(m)/_(z) (API⁻): 205.0[M−Pr_(i)].

Preparation 2

4-Ethyl-3-trifluoromethylbenzoic acid

Prepared as described in Preparation 1 from methyl4-ethyl-3-bromobenzoate (1.10 g; 4.52 mmol) and isolated as a whitesolid (923 mg; 93%).

¹H NMR (250MHz; (CD₃)₂CO) δ: 0.98 (3H, t, J=7 Hz), 2.60 (2H, q, J=7 Hz),7.36 (1H, d, J=8 Hz), 7.89 and 7.93 (1H, m), 7.96 (1H, br s); ^(m)/_(z)(API): 217.1 [M−H]⁷⁴.

Preparation 3

4-n-Propyloxy-3-trifluoromethylbenzoic acid

Prepared as described in Preparation I from methyl3-bromo-4-n-propyloxybenzoate (1.43 g; 5.23 mmol) and isolated as awhite solid (1.18 g; 9 1%).

₁H NMR (250MHz; (CD₃)₂SO) δ: 1.09 (3H, t, J=7 Hz), 1.79-1.93 (2H, m),4.26 (2H, t, J=6 Hz), 7.45 (1H, d, J=9 Hz), 8.19 (1H, d, J=2 Hz), 8.25and 8.28(1H, dd, J=9, 2 Hz); ^(m)/_(z) (API⁻): 203.1 [M−CO₂H].

Preparation 4

4-t-Butyl-3-trifluoromethylbenzoic acid

Prepared as described in Preparation I from methyl3-bromo-4-t-butylbenzoate (2.46 g; 9.1 mmol) and isolated as a whitesolid (1.55 g; 69%).

¹H NMR (250MHz; (CD₃)₂SO) δ: 1.42 (1H, s), 7.86-7.90 (1H, m), 8.09-8.13(1H, m), 8.23 (1H, d, J=2 Hz); ^(m)/_(z) (API⁻): 245.1 [M−H].

Preparation 5

4-Methoxy-3-trifluoromethylbenzoic acid

Prepared as described in Preparation 1 from methyl3-bromo-4-methoxybenzoate (6.9 g; 28.1 mmol) and isolated as needlesfrom aq. EtOH (4.61 g; 74%).

¹H NMR (250MHz; (CD₃)₂SO) δ; 3.78 (3H, s), 7.18 (1H, d, J=9 Hz), 7.90(1H, d, J=2 Hz), 7.98 and 8.02 (1H, dd, J=9, 2 Hz), 12.70-13.10 (1H, brs, exchangeable);

^(m)/_(z) (API⁻): 219.1 [M−H]; 175.1 [M−CO₂H].

Preparation 6

Methyl 3-Chloro-4-iso-propoxybenzoate

Methyl 3-chloro-4-hydroxybenzoate (5 g, 26.8 mmol) in DMF (45 ml) wastreated with potassium carbonate (7.41 g, 53.6 mmol), 2-iodopropane(3.85 ml, 40.2 mmol) and then stirred at 25° C. for 18 h. Work-up withethyl acetate gave the title compound (6.1 g).

Preparation 7

3-Chloro-4-iso-propoxybenzoic acid

Methyl 3-chloro-4-iso-propoxybenzoate (5.5 g, 24.1 mmol) was hydrolysedusing 1M NaOH (36 ml) in methanol (80 ml). Extraction and work-up withethyl acetate gave the title compound (4.3 g).

¹H NMR (DMSO-D₆) δ: 1.33 (6H, d), 4.79 (1H, m), 7.24 (1H, d), 7.87 (2H,m).

Preparation 8

3-Bromo-4-ethoxybenzoic acid

The title compound was prepared from 4-ethoxybenzoic acid in a mannersimilar to that of Procedure 1.

¹H NMR (DMSO-D₆) δ: 1.45 (3H, t, J=7 Hz), 4.26 (2H, q, J=7 Hz), 7.26(1H, d, J=9 Hz), 7.98 (1H, dd, J=2, 9 Hz), 8.12 (1H, d, J=2 Hz)

Preparation 9

3-Bromo-4-ethylbenzoic acid

The title compound was prepared from 4-ethylbenzoic acid.

¹H NMR (DMSO-D₆) δ: 1.20 (3H, t, J=7 Hz), 2.78 (2H, q, J=7 Hz), 7.50(1H, d, J=8 Hz), 7.90 (1H, dd, J=2, 8 Hz), 8.07 (1H, d, J=8 Hz)

Preparation 10

3-Cyano-4-iso-propylbenzoic acid

The title compound was prepared from 4-iso-propylbenzoic acid similar tothat described in Procedure 5.

¹H NMR (DMSO-D₆) δ: 1.07 (6H, d, J=7 Hz), 3.13 (1H,m, overlapped), 7.48(1H, d, J=7 Hz), 7.96 (1H, dd, J=2, 8 Hz), 8.00 (1H, d, J=2 Hz).

Preparation 11

4-Methoxy-3-trifluoromethylbenzoic acid

The title compound was prepared from 3-bromo-4-methoxybenzoic acid andpotassium trifluoroacetate in a manner similat to that of Procedures 3and 4.

¹H NMR (DMSO-D₆) δ: 3.78 (3H, s), 7.18 (1H, d, J=9 Hz), 7.90 (1H, d, J=2Hz), 8.00 (1H, dd, J=2, 9 Hz), 12.70-13.10 (1H, br, exchangeable)

Preparation 12

4-Methoxy-3-trifluoromethylbenzoyl chloride

The title compound was prepared from 4-methoxy-3-trifluoromethylbenzoicacid with oxalyl chloride and DMF in chloroform at room temperature [D.Levin, Chem. Br., 1977, 20] followed by evaporation in vacuo.

Preparation 13

Methyl 3-Bromo-4-iso-propoxybenzoate

Methyl 3-bromo-4-hydroxybenzoate (2.5 g, 10.8 mmol) in DMF (35 ml) wastreated with potassium carbonate (3.0 g, 21.6 mmol), 2-iodopropane(2.76, 21.6 mmol) and then stirred at 25° C. for 48 h. Work-up withethyl acetate gave the title compound (3.0 g).

¹H NMR (250MHz, CDCl₃) δ: 1.41 (6H, d, J=7 Hz), 3.89 (3H, s), 4.66 (1H,m), 6.90 (1H, d, J=8 Hz), 7.93 (1H, dd, J=8, 2 Hz), 8.22 (1H, d, J=2 Hz)

Preparation 14

Methyl 3-Cyano-4-iso-propoxybenzoate

Methyl 3-bromo-4-iso-propoxybenzoate (2.0 g, 7.3 mmol) andcopper(I)cyanide in N-methyl pyrrolidone (50 ml) were heated undervigorous reflux for 4 h. Work-up with ethyl acetate gave the titlecompound (1.0 g).

¹H NMR (250MHz, CDCl₃) δ: 1.56 (6H, d, J=7 Hz), 4.05 (3H, s), 4.88 (1H,m), 7.13 (1H, d, J=8 Hz), 8.31 (1H, dd, J=8, 2 Hz), 8.38 (1H, d, J=2 Hz)

Preparation 15

Methyl 3,5 Dichloro-4-ethoxybenzoate

The title compound was prepared in 69% yield from methyl3,5-dichloro-4-hydroxybenzoic acid and iodoethane in a manner similar tothat of Preparation 6.

¹H NMR (250MHz, CDCl₃) δ: 1.47 (3H, t, J=7 Hz), 3.91 (3H, s), 4.16 (2H,q, J=7 Hz), 7.96 (2H, s).

Preparation 16

3-Chloro-4-ethoxybenzoic acid

¹H NMR (DMSO-D₆) δ: 1.39 (3H, t, J=7 Hz), 4.20 (2H, q, J=7 Hz), 7.22(1H, d, J 7 Hz), 7.87 (2H, m).

Preparation 17

3-Bromo-4-iso-propoxybenzoic acid

The title compound was prepared using a method similar to that ofPreparation 7.

¹H NMR (DMSO-D₆) δ: 1.29 (6H, d, J=7 Hz), 4.77 (1H, sep, J=7 Hz), 7.20(1H, d, J=8 Hz), 7.87 (1H, dd, J=8, 2 Hz), 8.02 (1H, d, J=2 Hz), 12.92(1H, brs).

Preparation 18

4-iso-Propyloxy-3-trifluoromethylbenzoic acid

Methyl 3-bromo-4-iso-propyloxybenzoate (828 mg; 3.03 mmol) in DMF (25ml) was treated with potassium trifluoroacetate (922 mg; 6.06 mmol),copper (I) iodide (1.15 g; 6.06 mmol) and toluene (50 ml). The resultingmixture was heated at reflux for 1.5 h (Dean and Stark with removal ofca 50 ml of distillate) followed by reflux for 18 h then cooled. Themixture was poured into Et₂O (100 ml) and H₂O (100 ml). The two-phasemixture was stirred at room temperature for 0.5 h then filtered throughCelite. The two phases were separated, the aq. phase further extractedwith EtO (50 ml) and the organic extracts combined, washed withsaturated, aq. Na₂S₂O₃, H₂O, saturated brine, dried (MgSO₄) andevaporated in vacuo to give a brown oil. This was dissolved in MeOH (ca20 ml) and treated with 2M NaOH (2 ml; 4 mmol) and the resultingsolution heated at reflux for 3 h. The volatiles were removed in vacuoand the residue partitioned between EtOAc and H₂O. The phases wereseparated, the aq. phase acidified to pH1 with 2M HCl in the presence ofEtOAc and the phases separated. The aq. phase was further extracted withEtOAc, the extracts combined, washed with H₂O, saturated brine, dried(MgSO₄) and evaporated to dryness in vacuo to give the title compound asa white solid (671 mg; 89%).

¹H NMR (250MHz; (CD₃)₂CO) δ: 1.02 (6H, d, J=6 Hz), 4.53-4.63 (1H, m),7.01 (1H, d, J=9 Hz), 7.85-7.88 (2H, m); ^(m)/_(z) (API): 205.0[M−Pr^(i)].

Preparation 19

4-Ethyl-3-trifluoromethylbenzoic acid

Prepared as described in Preparation 18 from methyl4-ethyl-3-bromobenzoate (1.10 g; 4.52 mmol) and isolated as a whitesolid (923 mg; 93%).

¹H NMR (250MHz; (CD₃)₂CO) δ: 0.98 (3H, t, J=7 Hz), 2.60 (2H, q, J=7 Hz),7.36 (1H, d, J=8 Hz), 7.89 and 7.93 (1H, m), 7.96 (1H, br s); ^(m)/_(z)(API): 217.1 [M−H].

Preparation 20

4-n-Propyloxy-3-trifluoromethylbenzoic acid

Prepared as described in Preparation 18 from methyl3-bromo-4-n-propyloxybenzoate (1.43 g; 5.23 mmol) and isolated as awhite solid (1.18 g; 91%).

¹H NMR (250MHz; (CD₃)₂SO) δ: 1.09 (3H, t, J=7 Hz), 1.79-1.93 (2H, m),4.26 (2H, t, J =6 Hz), 7.45 (1H, d, J=9 Hz), 8.19 (1H, d, J=2 Hz), 8.26(1H, dd, J=9,2 Hz)

Preparation 21

4-t-Butyl-3-trifluoromethylbenzoic acid

Prepared as described in Preparation 18 from methyl3-bromo-4-t-butylbenzoate (2.46 g; 9.1 mmol) and isolated as a whitesolid (1.55 g; 69%).

¹H NMR (250MHz; (CD₃)₂SO) δ: 1.42 (9H, s), 7.86-7.90 (1H, m), 8.09-8.13(1H, m), 8.23 (1H, d, J=2 Hz); ^(m)/_(z) (API): 245.1 [M−H].

Preparation 22

4-Azidobenzoic acid

To a solution of 4-aminobenzoic acid (2.00 g, 14.00 mmol) intrifluoroacetic acid (10 ml) at 5° C., was added sodium nitrite (3.50 g)portionwise, and the mixture allowed to stir for 30 min. Sodium azide(3.79 g,) was then added portionwise and the mixture stirred for afurther 30 min at 0° C. The mixture was diluted with water, and a whitesolid precipitated. The solid was filtered, washed with cold water anddried, to afford the title compound (1.66 g, 73%).

EXAMPLE 1

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamide,monohydrochloride

3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine (300 mg; 1.84mmol) was dissolved in dry tetrahydrofuran (10 ml) under argon andtreated with a solution of 3-bromo-4-methoxybenzoyl chloride (459 mg;1.84 mmol) in dry tetrahydrofuran (10 ml). The mixture was stirred atambient temperatures for 18 h and the product (720 mg; 95%) collected byfiltration washed with tetrahydrofuran and dried.

¹H NMR [250MHz; (CD₃)₂SO] 67 : 3.03 (3H, s), 3.29 (2H, br m), 3.71 (2H,br m), 4.06 (3H, s), 4.56 (2H, br m), 7.39 (1H, d, J=9 Hz), 8.17-8.21(2H, m), 8.39 (1H, d, J=2 Hz), 8.91 (1H, d, J=2 Hz); ^(m)/_(z) (API):376, 378.

EXAMPLE 2

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-benzamide

3-Amino-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridine (314 mg, 1.9 mmol)was dissolved in dichloromethane (10 ml) and treated sequentially withtriethylamine (214 mg; 2.1 mmol) and benzoyl chloride (297 mg; 2.1mmol). The mixture was stirred at ambient temperature until tlc showedno starting material remaining. The reaction mixture was washed withsaturated aqueous sodium hydrogen carbonate, water, saturated brine,dried (anhydrous magnesium sulphate) and evaporated to dryness underreduced pressure. Chromatography through silica gel, eluting withmethanol in dichloromethane (0 to 50% methanol gradient), gave the titlecompound as an off-white foam (269 mg; 52%)

¹H NMR [250MHz; (CD₃)₂SO] δ: 2.47 (3H, s), 2.79 and 2.97 (each 2H, t,J=6 Hz), 3.62 (2H, br s), 7.48-7.74 (3H, m), 8.02 (1H, d, J=2 Hz),8.08-8.11 (2H, m), 8.80 (1H, d, J =2 Hz); ^(m)/_(z) (API): 268.1 (M+H)⁺;266.2 (M−H)⁻

EXAMPLE 3

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2-methoxy-4-t-butylbenzamide,monohydrochloride

Prepared as described in Example 1, using 4-t-butyl-2-methoxybenzoylchloride, in 89% yield.

¹H NMR [250MHz, (CD₃)₂SO] δ: 1.21 (9H, s), 2.80 (3H, s), 3.05 (2H, brm), 3.46 (2H, br m), 3.83 (3H, s), 4.32 (2H, br m), 6.97-7.02 (2H m),7.49 (1H, d, J=8 Hz), 7.99 (1H, br d), 8.61 (1H, d, J=2 Hz), 10.19 (1H,s, exchangeable), 10.90-11.40 (1H, br, exchangeable); ^(m)/_(z) (API):352.3 (M−H)⁻

EXAMPLE 4

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propoxybenzamide,monohydrochloride

Prepared as described in Example 1 from 4-isopropyloxybenzoyl chloridein 91% yield.

¹H NMR [250MHz, (CD₃)₂SO)] δ: 1.14 (6H, d, J=6 Hz), 2.75 (3H, s), 2.93(2H, br m), 3.53 (2H, br m), 4.23 and 4.34 (each 1H, 2 br m's),4.54-4.63 (1H, m), 6.89 (2H, d, J=9 Hz), 7.88 (2H, d, J=9 Hz), 7.94 (1H,d, J=2 Hz), 8.63 (1H, d, J=2 Hz), 10.25 (1H, s, exchangeable), 11.00(1H, br s, exchangeable); ^(m)/_(z) (API): 324.2 (M−H)⁻

EXAMPLE 5

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxybenzamide, monohydrochloride

Prepared as described in Example 1 from 4-ethoxybenzoyl chloride in 92%yield.

¹H NMR [250MHz, (CD₃)₂SO] δ: 1.54 (3H, t, J=7 Hz), 3.10 (3H, s), 3.34(2H, br m), 3.78 (2H, br m), 4.31 (2H, q, J=7 Hz), 4.62 (2H, br m), 7.25(2H, d, J=9 Hz), 8.18 (2H, d, J=9 Hz), 8.29 (1H, d, J=2 Hz), 8.98 (1H,d, J=2 Hz), 10.61 (1H, s, exchangeable), 11.35 (1H, br s, exchangeable);^(m)/_(z) (API): 310.2 (M−H)⁻

EXAMPLE 6

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2-methoxy-5-pivaloylbenzamide,monohydrochloride

Prepared as described in Example 1 from 2-methoxy-5-pivaloylbenzoylchloride in 91% yield.

¹H NMR [250MHz, (CD₃)₂SO] δ: 1.34 (9H, s), 2.93 (3H, s), 3.12 (2H, brm), 3.71 (2H, br m), 3.98 (3H, s), 4.41 and 4.52 (each 1H, 2 br m's),7.28 (1H, d, J=9 Hz), 8.06-8.12 (3H, m), 8.75 (1H, br d), 10.49 (1H, s,exchangeable), 11.30-11.70 (1H, br, exchangeable); ^(m)/_(z) (API): 382(M+H)⁺

EXAMPLE 7

N-(6-Methyl-5,6,7,8-tetrabydro[1,6]naphthyridin-3-yl)-3-trifuoro methylbenzamide, monohydrochloride

Prepared as described in Example 1 from 3-trifluoromethylbenzoylchloride in 91% yield.

¹H NMR [250MHz, (CD₃)SO] δ: 2.89 (3H, s), 3.15 (2H, br m), 3.55 (2H, brm), 4.42 (2H:, br m), 7.70-8.31 (5H, m), 8.78 (1H, d, J=2 Hz); ^(m)/_(z)(API): 336.2 (M+H)⁺

EXAMPLE 8

N-(6-Benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4methoxybenzamide

3-Bromo-4-methoxybenzoic acid (270 mg; 1.17 mmol) was dissolved inN,N-dimethylformamide (5 ml), the solution was cooled to 0-5° C. andtreated with 1-hydroxybenzotriazole(158 mg; 1.17 mmol) then1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (224 mg;1.17 mmol) and the mixture stirred at 0-5° C. for 0.5 h and treated witha solution of 3-amino-6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridine (255mg; 1.06 mmol) in DMF (5 ml). The reaction mixture was stirred atambient temperature for 72 h then diluted with dichloromethane (100 ml).The resulting mixture was washed with water (5×25 ml), saturated brine,dried (anhydrous magnesium sulfate) and evaporated to dryness in vacuoto yield a mobile, brown oil, which on trituration under 60-80° C.petroleum ether gave a biege powder, which was collected by filtration,washed with 60-80° C. petroleum ether and dried in air.Recrystallisation from ethyl acetate 60-80° C. petroleum ether gave thetitle compound as a beige powder (236 mg; 49%), m.p. 214-215° C.

¹H NMR [250MHz, (CD₃)₂SO] δ: 2.80, 2.87, 3,62 and 3.72 (each 2H, 4 brm), 3.95 (3H, s), 7.27 (1H, d, J=9 Hz), 7.34-7.39 (5H, m), 7.87 (1H, brs), 8.00 and 8.04 (1H, dd, J=9 and 2 Hz), 8.24 (1H, d, J=2 Hz), 8.65(1H, d, J=2 Hz).

^(m)/_(z) Found 451.0895. C₂₃H₂₂BrN₃O₂ requires 451.0895. Found: Br,17.90% C₂₃H₂₂BrN₃O₂ requires: Br, 17.66%.

The following Examples were prepared in a manner similar to that ofExample 1.

EXAMPLE 9

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide,monohydrochioride

¹H NMR [250MHz; D₂O] δ: 3.11 (3H, s), 3.26 (2H, br m), 3.40-4.10 (2H, brm), 3.87 (3H, s), 4.30-4.70 (2H, br m), 7.17 (1H, d, J=9 Hz), 7.92 (1H,m), 7.98-7.80 (2H, m), 8.50 (1H, d, J=2 Hz); ^(m)/_(z) (API): 366.1[M+H]

EXAMPLE 10

N-(6-Methyl-5,6,7,8-tetrahydrol[1,6]naphthyridin-3-yl)-4-t-butylbenzamide,monihydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.27 (9H, s), 3.10 (3H, s), 3.22 (2H, brm), 3.75 (2H, br m), 4.50 (2H, br m), 7.56 (2H, d, J=8 Hz), 7.75 (2H, d,J=8 Hz), 7.93 (1H, d, J=2 Hz), 8.56 (1H, d, J=2 Hz); ^(m)/_(z) (API):324.2 [M+H]⁺

EXAMPLE 11

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide,monohydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.34 (3H, t, J=7 Hz), 3.16 (3H, br s), 3.23(2H, br m), 3.40-4.15 (2H, br m), 4.02 (2H, q, J=7 Hz), 4.54 (2H, br),6.92 (1H, d, J=9 Hz), 7.62 and 7.65 (1H, dd, J=9 and 2 Hz), 7.78 (1H, d,J=2 Hz), 7.86 (1H, d, J=2 Hz), 8.41 (1H, d, J=2 Hz); ^(m)/_(z) (API):390 (M); 392 [M+H]⁺

EXAMPLE 12

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamide,monohydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.28 (6H, d, J=6 Hz), 3.07 (3H, s), 3.19(2H, br), 3.35-4.00 (2H, br), 4.47 (2H, br), 4.55-4.75 (1H, m), 7.05(1H, d, J=9 Hz), 7.66 and 7.70 (1H, dd, J=9 and 2 Hz), 7.84 (1H, d, J=2Hz), 7.86 (1H, d, J=2 Hz), 8.44 (1H, d, J=2 Hz); ^(m)/_(z) (API): 404.1(M)⁺, 406 (M+H)⁺

EXAMPLE 13

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide,hydrochloride

¹H NMR [250MHz; D₂O] δ: 2.97 (3H, s), 3.05 (2H, br), 3.20-4.00 (2H, br),4.36 (2H, br), 4.68 (3H, s), 6.79 (1H, d, J=9 Hz), 7.44-7.47 (2H, m),7.65 (1H, br s), 8.17 (1H, br s); ^(m)/_(z) (API): 332.2 [M+H]⁺

EXAMPLE 14

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl benzamide

Prepared as described in Example 1 from 4-ethylbenzoyl chloride,purified by chromatography of the free base through SiO₂, eluting withmixtures of methanol in dichloromethane, and isolated in 23% yield.

¹H NMR [250MHz; CD₃OD] δ: 1.09 (3H, t, J=8 Hz), 2.32 (3H, s), 2.56 (2H,q, J=8 Hz), 2.69 (2H, t, J=6 Hz), 2.84 (2H, t, J=6 Hz), 3.49 (2H, s),7.19 (2H, d, J=8 Hz), 7.70 (2H, d, J=8 Hz), 7.81 (1H, d, J=2 Hz), 8.48(1H, d, J=2 Hz);

^(m)/_(z) (API): 296.2 [M+H]⁺

EXAMPLE 15

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-cyclohexylbenzamide

Prepared as described in Example 1 from 4-cyclohexylbenzoyl chloride andpurified as described in Example 15. The title compound was isolated in70% yield as the free base.

¹H NMR [250MHz; CD₃OD] δ: 1.20-1.26 (5H, m), 1.70-2.00 (5H, m), 2.48(3H, s), 2.50-2.70 (1H, m), 2.84 (2H, t, J=6 Hz), 3.00 (2H, t, J=6 Hz),3.65 (2H, s), 7.34 (2H, d, J=8 Hz), 7.86 (2H, d, J=8 Hz), 7.96 (1H, d,J=2 Hz), 8.67 (1H, d, J=2 Hz);

^(m)/_(z) (API): 350.2 [M+H]⁺

EXAMPLE 16

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-benzoylbenzamide

Prepared as described in Example 1. The crude hydrochloride salt wasdissolved in water, neutralised with saturated aqueous sodium hydrogencarbonate and the free base extracted into dichloromethane. The organicextracts were combined, washed with saturated brine, dried (magnesiumsulphate) and evaporated to dryness to give the title compound in 71%yield.

1H NMR [250MHz; CD₃OD] δ: 2.45 (3H, s), 2.81 (2H, t, J=6 Hz), 2.97 (2H,t, J=6 Hz), 3.62 (2H, s), 7.08-8.04 (1OH, m), 8.63 (1H, d, J=2 Hz);^(m)/_(z) (API): 372.2 [M+H]⁺

EXAMPLE 17

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-ylcarboxamide

Prepared as described in Example 1 from2,3-dihydrobenzofuran-5-yl-carbonyl chloride and purified as describedin Example 15 to give the title compound in 16% yield.

1H NMR [250MHz; CD₃OD] δ: 2.39 (3H, s), 2.75 (2H, t, J=6 Hz), 2.90 (2H,t, J=6 Hz), 3.15 (2H, t, J=9 Hz), 3.54 (2H, s), 4.53 (2H, t, J=9 Hz),6.70 (1H, d, J=8 Hz), 7.63 and 7.67 (1H, dd, J=8 and 2 Hz), 7.71 (1H,br), 7.84 (1H, d, J=2 Hz), 8.52 (1H, d, J 2 Hz); ^(m)/_(z) (API): 310.2[M+H]³⁰

EXAMPLE 18

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-t-butyl-3-trifluoromethylbenzamide

Prepared as described in Example 1 from 4-t-butyl-3-trifluoromethylchloride and purified as described in Example 15. The title compound wasobtained in 63% yield.

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.37 (9H, s), 2.28 (3H, s), 2.61 (2H, t,J=6 Hz), 2.78 (2H, m), 3.44 (2H, s), 7.80-7.85 (2H, m), 8.08-8.18 (1H,m), 8.24 (1H, m), 8.59 (1H, d, J=2 Hz); ^(m)/_(z) (API): 390.2 [M−H]⁺

EXAMPLE 19

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propylbenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.19 (6H, d, J=7 Hz), 2.87-2.96 (1H, m),3.06 (3H, s), 3.21 (2H, br m), 3.40-3.90 (2H, m), 4.48 (2H, br m), 7.40(2H, d, J=8 Hz), 7.74 (2H, d, J=8 Hz), 7.92 (1H, d, J=2 Hz), 8.54 (1H,d, J=2 Hz); ^(m)/_(z) (API): 310.2 [M+H]⁺

EXAMPLE 20

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-nitrobenzamidehydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.15 (3H, t, J=7 Hz), 2.94 (3H, s), 3.05(2H, br m), 3.56 (2H, br m), 3.97 (2H, q, J=7 Hz), 4.34 (2H, br m), 7.02(1H, d, J=9 Hz), 7.71 (1H, m), 7.74 and 7.78 (1H, dd, J=9 and 2 Hz),8.02 (1H, d, J=2 Hz), 8.25 (1H, d, J=2 Hz);

^(m)/_(z) (API): 357.1 [M+H]⁺

EXAMPLE 21

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-1-butylbenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.16 (9H, s), 2.93 (3H, s), 2.93-3.20 (2H,br m), 3.54 (2H, br m), 4.32 (2H, br m), 7.23 (1H, d, J=8 Hz), 7.55-7.58(1H, br m), 7.76 (1H, br), 7.81 (1H, br), 8.38 (1H, br); ^(m)/_(z) (API)402.1, 404.0 (M⁺)

EXAMPLE 22

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 0.94 (3H, t, J=7 Hz), 2.30-2.60 (2H, m),2.90-3.28 (5H, m), 3.59 (2H, br m), 4.40 (2H, br m), 7.05 (1H, d, J=8Hz), 7.50-7.65 (1H, m), 7.73 (1H, d, J=1 Hz), 7.81 (1H, m), 8.36 (1H, d,J=2 Hz); ^(m)/_(z) (API) 374.0, 376.0 (M⁺)

EXAMPLE 23

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 3.22 (3H, s), 3.25-3.45 (2H, m), 3.60-3.95(2H, m), 3.97 (3H, s), 4.64 (2H, br m), 7.20 (1H, d, J=9 Hz), 7.90-8.20(3H, m), 8.46 (1H, m);

^(m)/_(z) (API): 323.1 (M+H)⁺

EXAMPLE 24

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-n-propyl-oxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.01 (3H, t, J=7 Hz), 1.73-1.76 (2H, m),3.10-3.40 (5H, m), 3.55-4.10 (4H, 2m), 4.40-4.80 (2H, m), 6.89 (1H, d,J=9 Hz), 7.68 and 7.71 (2×1H, m), 7.88 (1H, d, J=2 Hz), 7.94 (1H, m),8.51 (1H, d, J=2 Hz);

^(m)/_(z) (API): 404.1, 406.0 (M⁺)

EXAMPLE 25

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3,5-dichloro-4-methoxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 3.13 (3H, s), 3.20-3.40 (2H, m), 3.50-4.10(2H, br m), 3.82 (3H, s), 4.40-4.70 (2H, br m), 7.68 (2H, s), 7.89 (1H,d, J=2 Hz), 8.49 (1H, d, J=2 Hz); ^(m)/_(z) (API): 366.1 (MH^(⊕))

EXAMPLE 26

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propylbenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.17 (6H, d, J=7 Hz), 3.18 (3H, s),3.20-3.40 (3H, m), 3.50-4.10 (2H, br m), 4.40-4.70 (2H, br m), 7.40 (1H,d, J=8 Hz), 7.80 and 7.84 (2×1H, m), 8.02 (1H, d, J=1 Hz), 8.09 (1H, m),8.71 (1H, d, J=2 Hz);

^(m)/_(z) (API): 386.1, 388.1 (MH^(⊕)).

EXAMPLE 27

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-n-propyloxy-3-trifluoromethylbenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 0.75 (3H, t, J=7 Hz), 1.40-1.60 (2H, m),2.95 (3H, s), 2.30-3.10 (2H, br m), 3.30-3.90 (4H, br m), 4.20-4.60 (2H,br m), 6.80 (1H, d, J=9 Hz), 7.70-7.90 (4H, m), 8.34 (1H, br s);^(m)/_(z) (API): 394.1 (M+H⁺)

EXAMPLE 28

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-iodo-4-methoxybenzamidehydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 3.20 (3H, s), 3.34 (2H, br m), 3.85 (3H,s), 3.60-4.10 (2H, br m), 4.50-4.80 (2H, br m), 6.95 (1H, d, J=9 Hz),7.79 and 7.82 (1H, dd, J=9, 2 Hz), 7.96 (1H, d, J=2 Hz), 8.12 (1H, d,J=2 Hz), 8.51 (1H, d, J=2 Hz);

^(m)/_(z) (API): 424.0 (M+H⁺).

EXAMPLE 29

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propyl-3-trifluoromethylbenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 0.87 (6H, d, J=7 Hz), 2.80-3.10 (6H, m),3.20-3.80 (2H, br m), 4.10-4.50 (2H, m), 7.33 (1H, d, J=8 Hz), 7.60-7.80(3H, m), 8.32 (1H, d);

^(m)/_(z) (API): 378.1 (MH^(⊕)), 376.2 [M−H].

EXAMPLE 30

N-(6-Methyl-5,6,7,8-tetrahydro[1,61naphthyridin-3yl)-3-cyano-4-n-propyloxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 0.97 (3H, t, J=7 Hz), 1.65-1.81 (2H, m),3.15 (3H, s), 3.20-3.50 (2H, m), 3.50-4.20 (2H, m), 4.05 (2H, t, J=7Hz), 4.40-4.80 (2H, m), 7.11 (1H, d, J=9 Hz), 7.91-7.99 (2H, m), 8.08(1H, d, J=2 Hz), 8.64 (1H, d, J=2 Hz);

^(m)/_(z) (API): 351.2 (MR^(⊕)), 307.2 [M−Pr]

EXAMPLE 31

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.25 (3H, t, J=7 Hz), 2.99 (3H, s),3.10-4.00 (41H, m), 4.09 (2H, q, J=7 Hz), 4.20-4.90 (2H, m), 7.06 (1H,d, J=10 Hz), 7.90-7.94 (21H, m), 8.08 (1H, d, J=2 Hz), 8.71 (1H, d, J=2Hz); ^(m)/_(z) (API⁺): 337.2 (MH), 307.2 [M−Et].

EXAMPLE 32

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.08 (3H, t, J=7 Hz), 2.90 (3H, s),2.90-3.15 (2H, br m), 3.25-3.70 (21H, br m), 3.77 (2H, q, J=7 Hz),4.10-4.50 (2H, br m), 6.69 (1H, d ,J=9 Hz), 7.31-7.35 (21H, m), 7.63(1H, d, J=2 Hz), 8.19 (1H, d, J=2 Hz);

^(m)/_(z) (API⁺): 346.1 (MH), 344.3 [M−H]

EXAMPLE 33

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.35 (6H, d, J=6 Hz), 3.14 (3H, s), 3.32(2H, br m), 3.45-3.90 (2H, br m), 4.40-4.70 (2H, br m), 4.69 (1H, m),7.16 (1H, d, J=9 Hz), 7.70-7.74 (1H, dd, J=9, 2 Hz), 7.79 (1H, d, J 2Hz), 8.01 (1H, d, J=2 Hz), 8.63 (1H, d, J=2 Hz); ^(m)/_(z) (API⁺): 360.1(MH).

EXAMPLE 34

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 3.09 (3H, s), 3.15-3.30 (2H, br m),3.40-4.00 (2H, br m), 3.82 (3H, s), 4.35-4.70 (2H, br m), 7.06 (1H, t,J=9 Hz), 7.43 and 7.47 (1H, dd, J 12,2 Hz), 7.56 (1H, br d, J=9 Hz),7.90(1H, d, J=2 Hz), 8.46 (1H, d, J=2 Hz);

^(m)/_(z) (API⁺): 314.2 [M−H], 316.1 (MH).

EXAMPLE 35

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl]-4-ethyl-3-trifluoromethylbenzamide

Prepared as described in Example 1 from 4-ethyl-3-trifluoromethylbenzoyl chloride in 48% yield. Basification and purification bychromatography through SiO₂, eluting with a mixture of containing 10%0.880 aq. NH, in MeOH and DCM (1:9), gave the title compound as the freebase in 16% yield.

¹H NMR [250MHz; CD₃OD] δ: 1.19 (3H, t, J=7 Hz), 2.40 (3H, s), 2.68-2.84(4H, m), 2.92 (2H, t, J=6 Hz), 3.58 (2H, br s), 7.51 (1H, d, J=8 Hz),7.90 (1H, d, J=2 Hz), 8.01 and 8.04 (1H, br dd), 8.14 (1H, br d), 8.56(1H, d, J=2 Hz);

^(m)/_(z) (API⁺): 362.2 [M−H], 364.2 (MH).

EXAMPLE 36

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propyloxy-3-trifluoromethylbenzamide,hydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 1.14 (6H, d, J=6 Hz), 2.95-3.25 (5H, m),3.40-4.00 (2H, br m), 4.20-4.60 (3H, br m), 6.96 (1H, d, J=9 Hz),7.75-7.95 (3H, m), 8.44 (1H, br s); ^(m)/_(z) (API⁺): 394.1 (MH), 350.1[M−Pr^(i].)

EXAMPLE 37

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-iodo-4-methylbenzamidehydrochloride

¹H NMR [250MHz; (CD₃)₂SO] δ: 2.60 (3H, s), 3.09 (3H, brd), 3.10-3.80(4H, m), 4.55, 4.71 (2H, br m), 7.67 (1H, d, J=9 Hz), 8.10 (1H, dd,J=9,2 Hz), 8.35 (1H, d, J=2 Hz), 8.59 (1H, d, J=2 Hz), 9.00 (1H, d, J=2Hz), 10.84 (1H, s), 11.13 (1H, br);

^(m)/_(z) (API⁺): 408.0 (MH⁺, 88%)

EXAMPLE 38

N-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-azido-3-iodo-benzamide

Prepared from D4 in a manner similar to that described in Example 8 andP22.

^(m)/_(z) (API⁺): 435.2 (MH+, 85%).

EXAMPLE 39

N-(2-Bromo-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide

The title compound was prepared in 6% yield from D6.

¹H NMR (250MHz, d₆DMSO) δ: interalia 1.34 (3H, t, J=7 Hz), 2.36 (3H, s),2.73 (2H, m), 2.85 (2H, m), 3.52 (2H, s), 4.16 (2H, q, J=7 Hz), 7.20(1H, d, J=8 Hz), 7.95 (1H, dd, J=8, 2 Hz), 8.18 (1H, d, J=2 Hz), 10.09(1H, s); m/z (API⁺): 468/470/472 (MH⁺).

EXAMPLE 40

N-(2-Bromo-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide,hydrochloride

The title compound was prepared in 16% yield from the amine D6.

¹H NMR [free base] (250MHz, CDCl₃) 3: 2.49 (3H, s), 2.78 (2H, t, J=6Hz), 3.03 (2H, t, J=6 Hz), 3.60 (2H, s), 4.01 (3H, s), 7.14 (1H, d, J=9Hz), 8.08 (1H, dd, J=9,2 Hz), 8.16 (1H, d, J=2 Hz), 8.32 (1H, brs), 8.49(1H, s); m/z (API⁺): 444/446 (MH⁺).

EXAMPLE 41

N-(2,6-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxy-benzamide

The title compound was prepared in 36% yield from the amine D7.

¹H NMR (250MHz, CDCl₃) δ: 1.52 (3H, t, J 7 Hz), 2.49 (3H, s), 2.53 (3H,s), 2.78 (2H, t, J=6 Hz), 3.00 (2H, t, J=6 Hz), 3.55 (2H, s), 4.19 (2H,q, J=7 Hz), 6.96 (1H, d, J=8 Hz), 7.76-7.84 (3H, m), 8.06 (1H, d, J=2Hz); m/z (API⁺): 404/406 (MH⁺).

EXAMPLE 42

N-(2,6-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trinfluoromethylbenzamide.

The title compound was prepared in 29% from the amine D7.

¹H NMR (250MHz, CDCl₃) δ: 2.48 (3H, s), 2.53 (3H, s), 2.78 (2H, t, J=6Hz), 3.01 (2H, t, J=6 Hz), 3.56 (2H, s), 4.00 (3H, s), 7.12 (1H, d, J=8Hz), 7.73 (1H, brs), 7.82 (1H, s), 8.04-8.09 (2H, m); m/z (API⁺): 380(MH⁺).

EXAMPLE 43

N-(2-Cyano-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide

A sample of the compound prepared in Example 40 (86 mg, 0.19 mmol) wasdissolved in N-methylpyrrolidinone (2 ml) and copper (I) cyanide (50 mg)added. The mixture was heated in an oil bath at 180° C. under argon for5 h. After cooling, the mixture was diluted with water and ethylacetate, filtered and the organic layer washed with brine, dried (MgSO₄)and evaporated to an oil. Purification by chromatography on silica geleluting with dichloromethane:methanol: aq ammonia (0.880) gave the titlecompound as a white solid (7.5 mg).

¹H NMR (250MHz, CDCl₃) δ: 2.51 (3H, s), 2.80 (2H, t, J=6 Hz), 3.05 (2H,t, J=6 Hz), 3.69 (2H, s), 4.01 (3H, s), 7.14 (1H, d, J=9 Hz), 8.06 (1H,dd, J=9, 2 Hz), 8.20 (1H, d, J =2 Hz), 8.28 (1H, brs), 8.55 (1H, s); m/z(API⁺): 391 (MH⁺).

EXAMPLE 44

N-(2-Chloro-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamide

¹H NMR (CDCl₃) δ: 1.53 (3H, t), 2.50 (2H, s), 2.78 (2H, t), 3.01 (2H,t), 3.62 (2H, s), 4.20 (2H, q), 6.98 (1H, d), 7.81 (1H, dd), 8.11 (1H,d), 8.25 (1H, s), 8.52 (1H, s); m/z (API⁺): 424.1 (M⁺; 100%).

EXAMPLE 45

N-(2-Chloro-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide

¹H NMR (CDCl₃) δ: 2.51 (3H, s), 2.79 (2H, t), 3.02 (2H, t), 3.63 (2H,s), 4.01 (3H, s), 7.14 (1H, d), 8.06 (1H, dd), 8.15 (1H, d), 8.26 (1H,s), 8.55 (1H, s);

m/z (API⁺): 400.2 (MH⁺, 100%).

Biological Data

All the compounds showed in vitro binding affinity in this test withpKi's in the range 6-9. Examples 1, 3, 10, 11, 12, 20, 28, 30, 33 and 36had a pKi>8.0.

Binding Assay Method

WO 92/22293 (SmithKline Beecham) discloses compounds havinganti-convulsant activity, including inter alia the compoundtrans-(+)-6-acetyl-4S-(4-fluorobenzoylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3R-ol(herein referred to as Compound A). It has been found that the compoundsof WO 92/22293 bind to a novel receptor obtainable from rat forebraintissue, as described in WO 96/18650 (SmithKline Beecham). The affinityof test compounds to the novel receptor site is assessed as follows.

Method

Whole forebrain tissue is obtained from rats. The tissue is firsthomogenised in buffer (usually 50 mM Tris/HCl, pH 7.4). The homogenisedtissue is washed by centrifugation and resuspension in the same buffer,then stored at −70° C. until used.

To carry out the radioligand binding assay, aliquots of tissue preparedas above (usually at a concentration of 1-2 mg protein/ml) are mixedwith aliquots of [3H]-Compound A dissolved in buffer. The finalconcentration of [3H]-Compound A in the mixture is usually 20 nM. Themixture is incubated at room temperature for 1 hour. [3H]-Compound Abound to the tissue is then separated from unbound [3H]-Compound A byfiltration through Whatman GF/B glass fibre filters. The filters arethen washed rapidly with ice-cold buffer. The amount of radioactivitybound to the tissue trapped on the filters is measured by addition ofliquid scintillation cocktail to the filters followed by counting in aliquid scintillation counter.

In order to determine the amount of “specific” binding of [3H]-CompoundA, parallel assays are carried out as above in which [3H]-Compound A andtissue are incubated together in the presence of unlabelled Compound A(usually 3 μM). The amount of binding of [3H]-Compound A remaining inthe presence of this unlabelled compound is defined as “non-specific”binding. This amount is subtracted from the total amount of[3H]-Compound A binding (i.e. that present in the absence of unlabelledcompound) to obtain the amount of “specific” binding of [3H]-Compound Ato the novel site.

The affinity of the binding of test compounds to the novel site can beestimated by incubating together [3H]-Compound A and tissue in thepresence of a range of concentrations of the compound to be tested. Thedecrease in the level of specific [3H]Compound A binding as a result ofcompetition by increasing concentrations of the compound under test isplotted graphically, and non-linear regression analysis of the resultantcurve is used to provide an estimate of compound affinity in terms ofpKi value.

MEST Test

The maximal electroshock seizure (MEST) threshold test in rodents isparticularly sensitive for detecting potential anticonvulsantproperties¹. In this model, anticonvulsant agents elevate the thresholdto electrically-induced seizures whilst proconvulsants lower the seizurethreshold.

Method

Mice (naive male, Charles River, U.K. CD-1 strain, 25-30 g) are randomlyassigned to groups of 10-20 and dosed orally or intraperitoneally at adose volume of 10 ml/kg with various doses of compound (0.3-300 mg/kg)or vehicle. Mice are then subjected at 30 or 60 min post dose to asingle electroshock (0.1 sec, 50 Hz, sine wave form) administered viacorneal electrodes. The mean current and standard error required toinduce a tonic seizure in 50% (CC₅₀) of the mice in a particulartreatment group is determined by the ‘up and down’ method of Dixon andMood (1948)². Statistical comparisons between vehicle- and drug-treatedgroups are made using the method of Litchfield and Wilcoxon (1949)³.

In control animals the CC₅₀ is usually 14-18 mA. Hence the first animalin the control group is subjected to a current of 16 mA. If a tonicseizure does not ensue, the current is increased for a subsequent mouse.If a tonic convulsion does occur, then the current is decreased, and soon until all the animals in the group have been tested.

The percentage increase or decrease in CC₅₀ for each group compared tothe control is calculated.

Studies are carried out using a Hugo Sachs Electronik Constant CurrentShock Generator with totally variable control of shock level from 0 to300 mA and steps of 2 mA are usually used.

Drugs are suspended in 1% methyl cellulose.

REFERENCES

1. Loscher, W. and Schmidt, D. (1988). Epilepsy Res., 2, 145-181

2. Dixon, W. J. and Mood, A. M. (1948). J. Amer. Stat. Assn., 43,109-126

3. Litchfield, J. T. and Wilcoxon, F.(1949). J. Pharmacol. exp. Ther.,96, 99-113

Results

Compounds of this invention dosed by the oral route as a suspension inmethyl cellulose and tested one hour post dosing showed an increase inseizure threshold. For example, at a dose of 10 mg/kg p.o. the compoundof Example 1 showed an increase of 177%, the compound of Example 2showed an increase of 97%, and the compound of Example 5 showed anincrease of 106%.

What is claimed is:
 1. A compound of formula (I) or pharmaceuticallyacceptable salt thereof:

where R¹ is hydrogen, C₁₋₆ alkyl optionally substituted by hydroxy orC₁₋₄alkoxy, or C₁₋₆ alkylphenyl; R² is hydrogen or up to threesubstituents selected from halogen, NO₂, CN, N₃, C₁₋₆ alkylO-, C₁₋₆alkylS-, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄alkyl-,C₁₋₆alkenyl, C₁₋₆alkynyl, CF₃, CF₃O, CF₃CO—, C₁₋₆alkylCO-,C₃₋₆cycloalkylCO-, C₃₋₆cycloalkyl-C₁₋₄alkylCO-, phenyl, phenoxy,benzyloxy, benzoyl, phenyl-C₁₋₄alkyl-, or —NR³R⁴ where R³ is hydrogen orC₁₋₄ alkyl, and R⁴ is hydrogen, C₁₋₄alkyl, —CHO, —CO₂C₁₋₄alkyl or—COC₁₋₄alkyl; or two R² groups form a saturated carbocyclic ringoptionally interrupted by oxygen; and X is selected from hydrogen,halogen, cyano, alkyl and alkoxy.
 2. A compound according to claim 1,selected from the group consisting of:N-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-benzamideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2-methoxy-4-t-butylbenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propoxybenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxybenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2-methoxy-5-pivaloylbenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-trifluoromethylbenzamide and its monohydrochlorideN-(6-benzyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-methoxybenzamideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-t-butylbenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamideand its monohydrochlorideN-(6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propyloxybenzamideand its monohydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-methoxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethyl benzamideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-cyclohexylbenzamideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-benzoylbenzamideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-2,3-dihydrobenzofuran-5-ylcarboxamideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-t-butyl-3-trifluoromethylbenzamideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propylbenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-ethoxy-3-nitrobenzamidehydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-t-butylbenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethylbenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-methoxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-n-propyl-oxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3,5-dichloro-4-methoxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-iso-propylbenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-n-propyloxy-3-trifluoromethylbenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-iodo-4-methoxybenzamidehydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6naphthyridin-3-yl)-4-iso-propyl-3-trifluoromethylbenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-n-propyloxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-cyano-4-ethoxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-ethoxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-chloro-4-iso-propyloxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-fluoro-4-methoxybenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl]-4-ethyl-3-trifluoromethylbenzamideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-iso-propyloxy-3-trifluoromethylbenzamide,hydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-iodo-4-methylbenzamidehydrochlorideN-(6-Methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-azido-3-iodo-benzamideN-(2-Bromo-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamideN-(2-Bromo-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide,hydrochlorideN-(2,6-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxy-benzamideN-(2,6-Dimethyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideN-(2-Cyano-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamideN-(2-Chloro-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-3-bromo-4-ethoxybenzamideN-(2-Chloro-6-methyl-5,6,7,8-tetrahydro[1,6]naphthyridin-3-yl)-4-methoxy-3-trifluoromethylbenzamide.3. A pharmaceutical composition for use in the treatment or prophylaxisof a disorder treatable or preventable with an anti-convulsive agent,migraine, neuralgia, trigeminal neuralgia, neuropathic pain, whichcomprises a compound according to claim 1 or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.
 4. A method of treatment or prophylaxis of a disorder treatableor preventable with an anti-convulsive agent, migraine, neuralgia,trigeminal neuralgia, neuropathic pain, comprising administering to thesufferer in need thereof an effective or prophylactic amount of acompound according to claim 1 or a pharmaceutically acceptable salt orsolvate thereof.
 5. A process for the preparation of a compoundaccording to claim 1, which comprises reacting a compound of formula(II)

where R^(1A) is R¹ as defined for formula (I) of claim 1 or a groupconvertible to R¹ and X is as defined for formula (I) of claim 1 with acompound of formula (III)

where Y is Cl or OH, and R^(2A) is R² as defined for formula (I) or agroup or groups convertible to R², and where required converting aR^(1A) or R^(2A) group to a R¹ or R² group, converting one X, R¹ or R²group to another X, R¹ or R² group, converting a salt product to thefree base or another pharmaceutically acceptable salt, or converting afree base product to a pharmaceutically acceptable salt.
 6. Apharmaceutical composition for use in the treatment or prophylaxis of adisorder treatable or preventable with an anti-convulsive agent,migraine, neuralgia, trigeminal neuralgia, neuropathic pain, whichcomprises a compound according to claim 2 or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptablecarrier.
 7. A method of treatment or prophylaxis of a disorder treatableor preventable with an anti-convulsive agent, migraine, neuralgia,trigeminal neuralgia, neuropathic pain, comprising administering to thesufferer in need thereof an effective or prophylactic amount of acompound according to claim 2 or a pharmaceutically acceptable salt orsolvate thereof.